CN105111209B - Aza-indoline compound and method for preparing same - Google Patents

Abstract

The invention relates to an aza-indoline compound and a method for preparing the same. The aza-indoline compound is 6-trifluoromethyl-2, 3-pyrroline [2, 3-b] pyridine, and 2-hydroxyl-5-trifluoromethyl pyridine is synthesized by means of 9-step reaction to obtain the aza-indoline compound. The aza-indoline compound and the method have the advantages that the aza-indoline compound is a novel phosphodiesterase inhibitor and has a broad application prospect in the aspect of diseases such as asthma; raw materials for the aza-indoline compound prepared by the aid of the method are inexpensive and are easily available, the method for synthesizing the raw materials is simple and is a novel method for synthesizing the raw materials to obtain the aza-indoline compound, and requirements of large-scale industrial production can be met.

Description

Azaindoline compound and preparation method thereof

Technical Field

The invention relates to the field of compound production, in particular to an azaindoline compound and a preparation method thereof.

Background

Azaindoline compounds are key intermediates in the preparation of Phosphodiesterase (PDE) inhibitors (preambles of azaindolines and benzoyl sulfated azaindolines: preambles of the formula [ cd ] azulen-9-one PDE4 inhibitors. tetrahedron Letters (2011),52(41), 5292. sup. 5296). The azaindoline compound is widely present in drug molecules with biological activity, and has wide application value in treating and prepaying diseases such as heart failure, asthma, impotence and the like. The compound is used as a parent to further synthesize more complex derivatives, thereby providing conditions for more widely researching the properties of the compound.

Disclosure of Invention

The technical problem to be solved by the invention is to provide an azaindoline compound.

Another technical problem to be solved by the present invention is to provide a method for producing the azaindoline compound.

In order to solve the technical problems, the technical scheme of the invention is as follows:

an azaindoline compound, 6-trifluoromethyl-2, 3-dihydropyrrole [2,3-b ] pyridine, the structural formula of which is shown in (I),

preferably, the hydrogen nuclear magnetic resonance spectrum data of the azaindoline compound, 6-trifluoromethyl-2, 3-dihydropyrrole [2,3-b ] pyridine is 3.216-3.173(t, 2H), 3.742-3.699(t,2H),6.888-6.884(d,1H),8.080(s, 1H).

The preparation method of the azaindoline compound takes 2-hydroxy-5-trifluoromethylpyridine as a starting material, and synthesizes a target compound through 9 steps of reaction, and comprises the following specific steps:

(1) nitrating a compound 12-hydroxy-5-trifluoromethyl pyridine to obtain a compound 2;

(2) the compound 2 is chlorinated to obtain a compound 3 under the action of phosphorus oxychloride;

(3) substituting dimethyl malonate for chlorine by the compound 3 under the action of sodium hydride to obtain a compound 4;

(4) the compound 4, dimethyl malonate substituted compound, is decarboxylated under acidity to obtain a compound 5;

(5) the Leimgruber-Batco synthesis method is carried out on the compound 5, and the compound 6 is synthesized in the first step;

(6) the compound 6 is synthesized into the indole compound 7 by a Leimgruber-Batco synthesis method through a nitro reduction in the second step;

(7) separating and purifying Boc on the compound 7 azaindole to obtain a compound 8;

(8) compound 8 by Pd (OH)₂Reducing to generate a compound 9 azaindoline;

(9) removing Boc group from the compound 9 by TFA to obtain a target compound 10; wherein,

the intermediate compound 6 in the preparation method of the azaindoline compound has a structural formula shown in (II),

the intermediate compound 7 in the preparation method of the azaindoline compound has a structural formula shown in (III),

the intermediate compound 8 in the preparation method of the azaindoline compound has a structural formula shown as (IV),

the intermediate compound 9 in the preparation method of the azaindoline compound has a structural formula shown in (V),

the specific reaction equation of the preparation method of the azaindoline compound is as follows:

the invention has the beneficial effects that:

the azaindoline compound 6-trifluoromethyl-2, 3-dihydropyrrole [2,3-b ] pyridine is a novel phosphodiesterase inhibitor and has wide application prospect in diseases such as asthma and the like; the preparation method has the advantages of cheap and easily-obtained raw materials and simple synthesis method, is a brand-new method for synthesizing azaindoline compounds, and is suitable for the requirement of large-scale industrial production.

Drawings

FIG. 1 is a HNMR spectrum of 6-trifluoromethyl-2, 3-dihydropyrrolo [2,3-b ] pyridine.

Detailed Description

In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description will be given with reference to specific embodiments.

Example 1

The preparation method of 6-trifluoromethyl-2, 3-dihydropyrrole [2,3-b ] pyridine comprises the following steps:

(1) dissolving 100g of the compound 1 in 400ml of concentrated sulfuric acid, adding the solution into a 2L three-neck bottle, and heating the solution until the internal temperature is raised to 80 ℃; slowly dropping 110g of concentrated nitric acid into a reaction system by using a dropping funnel, starting to heat the system, at the moment, transferring a reaction bottle from a hot bath to an air bath, controlling the dropping speed to keep the internal temperature within the range of 80-85 ℃ (the temperature is high, the yield is reduced, the temperature can be properly controlled by using a cold water bath), dropping for about 50 minutes (all 40-60 minutes), and then carrying out heat preservation reaction for 50 minutes (all 40-60 minutes) by using an oil bath; TLC shows that most raw materials are reacted, heating is stopped, the temperature is rapidly reduced to room temperature, the reaction solution is poured onto 1000g of crushed ice to obtain turbid solution, then Ethyl Acetate (EA) is used for extraction (500ml x 2), the organic phase is washed once with saturated brine, drying and concentration are carried out to obtain crude product, the crude product is added into Dichloromethane (DCM) (80ml), stirring is carried out for 5min, a small amount of unreacted raw materials are dissolved, filtering is carried out, a filter cake is washed with a small amount of DCM, then washed with EA and petroleum ether, and the filter cake is dried to obtain compound 2 which is light yellow solid. TLC information: ultraviolet color development, raw material Rf is 0.5, product Rf is 0.1. Developing agent: EA/1-2 drops of ammonia or DCM/MeOH 10/1 plus 1-2 drops of ammonia. The product was found to be 35 g, a pale yellow solid, 28% yield.

(2) Adding 52g of compound 2 into 150ml of phosphorus oxychloride, slowly adding 21g of quinoline while stirring, controlling the feeding speed so that the internal temperature does not exceed 50 ℃, slowly dissolving the compound 2, protecting the system by argon, heating in an oil bath, setting the external temperature to be 120 ℃, starting refluxing after 20-30 minutes, and keeping the system to slightly boil for reaction for 1.5 hours. TLC shows that the raw material reaction is finished, heating is stopped, the system is decompressed and concentrated to remove phosphorus oxychloride, then EA (400ml) is used for dissolving, 2N HCl (200ml x 2) is used for washing to remove quinoline, saturated sodium bicarbonate solution is used for washing to be neutral, and the organic phase is dried and concentrated to obtain the compound 3. TLC information: rf of raw material is 0.1, Rf of product is 0.7. Developing agent: PE/EA/═ 15/1. 50g of product were measured as a brown oil with a yield of 88%.

(3) 50g of compound 3 and 52.5g of dimethyl malonate are dissolved in 500ml of anhydrous tetrahydrofuran, the temperature of the system is reduced to-10 to-20 ℃ by dry ice ethanol under the protection of argon, 15.9g of sodium hydride is added in batches, and the internal temperature is controlled to be about 0 ℃. After completion, the reaction mixture was allowed to naturally warm to room temperature and allowed to react overnight for 16 hours. TLC showed the starting material was reacted and the reaction was quenched by pouring into saturated ammonium chloride solution (500ml), then extracted with ethyl acetate (500ml x 2), the organic phases were combined, washed once with water, dried and the solvent was dried to give compound 4 (crude product). TLC information: rf of raw material is 0.7, Rf of product is 0.15. Developing agent: PE/EA/═ 15/1. 97g of crude product was measured as a red oil.

(4) 97g of compound 4 was added to 10 times the volume of 10000ml of 4N HCl, the temperature of the oil bath was controlled at 120 ℃ and 125 ℃, and the mixture was heated to reflux overnight (16 hours, the reaction was slow and it had to be done overnight). TLC showed completion, the system was allowed to cool to room temperature, then the reaction was poured into 1000ml of cold water, extracted with EA (500ml x 3), the organic phases were combined, washed with saturated sodium bicarbonate to neutral or basic (400ml x 2), the organic phase was dried and the solvent was dried to give a red oil. The oily substance is transferred into a 50ml test tube and is stood for layering, the upper colorless transparent liquid is separated (the mineral oil in the sodium hydride in the step above), and the lower red liquid is the product compound 5. TLC information: rf of raw material is 0.3, Rf of product is 0.7. Developing agent: petroleum ether/ethyl acetate (PE/EA) ═ 5/1. 35 g of product was measured as a red oil in 77% yield.

(5) 30g of the compound 5 is added into 180ml of dimethylformamide dimethyl acetal (DMFDMA), the temperature of an oil bath is controlled at 110 ℃, the mixture is heated to reflux for reaction for 1 hour, water is added into a condensation tube without circulation, and the generated methanol is quickly volatilized and removed through a drying tube at the upper end of the condensation tube. TLC showed completion, and was concentrated under reduced pressure to remove the solvent to give compound 6 as a red oil which cooled to a red solid. TLC information: rf is 0.7, Rf is 0.5; developing agent: PE/EA/═ 5/1. The product was found to be 38 g, a red oil, crude.

(6) 65g of iron powder is added into a 2-liter three-neck bottle, added into 2N hydrochloric acid, and subjected to oil bath temperature control of 100 ℃ and reflux activation for 15 minutes. Acetic acid (40 ml) and ethanol (150ml) were added and the oil bath was controlled to a temperature of 95 deg.C and refluxed for a further 30 minutes. The compound 6 was added to the reaction system in portions, the addition rate was controlled to complete in about 40 to 60 minutes, and the reaction was continued under reflux for 1 hour. After TLC, ethyl acetate (400ml) was added, refluxing was continued for 10 min, the mixture was filtered while hot with celite, the filter cake was washed twice with hot ethanol and ethyl acetate, the filtrate was dark red, the solvent was removed by concentration, the residue was diluted with water (200ml) and ethyl acetate (300ml), the pH was adjusted to 8-9 with 2-3N sodium hydroxide solution (the acetate salt of the product was liberated), iron salts such as iron hydroxide were removed by filtration again, the chloride cake was washed with hot ethyl acetate, the filtrate was separated into layers, the organic phase was separated, the aqueous phase was extracted once with ethyl acetate, the organic phases were combined, dried and concentrated under reduced pressure to remove the solvent to give compound 7. TLC information: ultraviolet color development, raw material Rf is 0.5, product Rf is 0.2. Developing agent: PE/EA/═ 5/1. 17.8 g of product was measured as brown solid, yield: 66% (two steps).

(7) 9g of Compound 7 was dissolved in 100ml of dichloromethane, 13.7g of Boc anhydride and 6.4g of triethylamine were added, and the mixture was stirred at room temperature overnight (16 h). TLC showed complete reaction, after cooling, silica gel was added directly to mix and column purified (PE/EA) to give compound 8. TLC information: ultraviolet color development, raw material Rf is 0.2, product Rf is 0.6. Developing agent: PE/EA/═ 3/1. The product was measured to be 8.5 g, white solid, yield 62%.

(8) 4g of Compound 8 are dissolved in 100ml of ethanol, 1g of palladium hydroxide is added, the autoclave is replaced 5 times with hydrogen and the temperature is raised to 50 ℃ and the reaction is carried out overnight under a hydrogen pressure of 1 MPa. TLC and LCMS both showed complete reaction, the reaction was filtered through celite, the filtrate was concentrated and purified over short column (PE/EA) to afford clean product compound 9. TLC information: rf of raw material is 0.60, Rf of product is 0.55. Developing agent: PE/EA/═ 3/1. The product was measured as 4.3g, yellow oil, yield 100%.

(9) 4.3g of the compound 9 are dissolved in 25ml of dichloromethane and 10ml of trifluoroacetic acid are slowly added dropwise under the protection of argon, after which the reaction is carried out at room temperature for 3.5 hours. TLC showed complete reaction, the reaction was concentrated below 40 ℃ to remove the solvent, taken twice with dry dichloromethane (50 ml. times.2), the residue was adjusted to basic pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 ml. times.2), combined with organic phase and washed with waterDrying, and drying the solvent at a temperature of below 40 ℃ to obtain the compound 10, namely the target product. TLC information: rf of raw material is 0.55 and Rf of product is 0.3. Developing agent: PE/EA/═ 3/1. 2.3 g of product, yellow solid powder, purity > 96% and yield 82% were determined. As shown in figure 1, 6-trifluoromethyl-2, 3-dihydropyrrole [2,3-b ]]HNMR (CDCl) of pyridine₃) The spectrogram has hydrogen spectrum data as follows: 3.216-3.173(t, 2H), 3.742-3.699(t,2H),6.888-6.884(d,1H),8.080(s, 1H).

The specific reaction equation is as follows:

application test example

Male SD rats, aged 4-6 weeks for months, weighing 130-.

The first group, asthma group, was prepared by intraperitoneal injection of 1ml antigen solution (containing 100mg egg protein, inactivated Bordetella pertussis vaccine 5 x 10) into each rat⁹And 100mg of aluminum hydroxide dry powder) sensitization;

the second group, asthma treatment group, was a group in which each rat was gavaged with 1.2. mu.g/kg of the azaindoline compound obtained in example 1 every 12 hours, and three days later, each rat was intraperitoneally injected with 1ml of an antigenic solution (containing 100mg of egg protein, inactivated Bordetella pertussis vaccine 5 x 10)⁹And 100mg of aluminum hydroxide dry powder).

The results showed that the first group, asthma-group antigen challenge, immediately exhibited shortness of breath, flaccidity of limbs, sluggish movement or pronation, while the second group, asthma-treated group showed no significant response. The compound of the invention has certain inhibition effect on asthma.

The above detailed description of the azaindoline compound and the method of preparation thereof, with reference to specific embodiments, is illustrative and not restrictive, and several examples are set forth within the scope of the invention, such that variations and modifications within the spirit and scope of the invention are intended to be covered thereby.

Claims (1)

1. A preparation method of azaindoline compound, the structural formula of the azaindoline compound is shown as (I),

the method is characterized in that: taking 2-hydroxy-5-trifluoromethylpyridine as a starting material, synthesizing a target compound through a 9-step reaction, and specifically comprising the following steps:

(1) nitrating a compound 12-hydroxy-5-trifluoromethyl pyridine to obtain a compound 2;

(2) the compound 2 is chlorinated to obtain a compound 3 under the action of phosphorus oxychloride;

(3) substituting dimethyl malonate for chlorine by the compound 3 under the action of sodium hydride to obtain a compound 4;

(4) the compound 4, dimethyl malonate substituted compound, is decarboxylated under acidity to obtain a compound 5;

(5) the Leimgruber-Batco synthesis method is carried out on the compound 5, and the compound 6 is synthesized in the first step;

(6) the compound 6 is synthesized into the indole compound 7 by a Leimgruber-Batco synthesis method through a nitro reduction in the second step;

(7) separating and purifying Boc on the compound 7 azaindole to obtain a compound 8;

(8) compound 8 by Pd (OH)₂Reducing to generate a compound 9 azaindoline;

(9) removing Boc group from the compound 9 by TFA to obtain a target compound 10; wherein,